G-protein Cycle and its Regulation by RGS Proteins

G-protein Cycle and its Regulation by RGS Proteins Julia Weigandt G Proteins, also known asguanine nucleotide-binding proteins, are a family of membrane resident â€Å"go-between† proteins that are important molecular switches in the mediation of GPCR signalling1. In their inactive state, G-proteins exist as heterotrimeric complexes composed of ÃŽ ±, ÃŽ ² and ÃŽ ³-subunits. Upon its stimulation, a GPCR will catalyse the GDPà ¯Ã†â€™Ã‚  GTP exchange at GÃŽ ± leading to the dissociation of the trimer complex as a GÃŽ ±-subunit and the GÃŽ ²ÃŽ ³-dimer, both able to interact with a number of effector systems responsible for cellular responses. Upon hydrolysis of GTP to GDP+P by GÃŽ ±, the G-protein mediated signalling is terminated, whereby a group of proteins, the regulators of G-protein signalling (RGS) appear to play substantial role1,2. Every organ system utilises G-protein mediated signal transduction evoking such diverse outcomes as neurotransmission, immunity, cardiovascular function and hormone secretion3. Consequently, GPCRs present a variety of opportunities as therapeutic targets for treating cancer, cardiac dysfunction, central nervous system disorders and pain. In fact, drugs targeting members of this protein superfamily account for 40% of all prescription pharmaceuticals on the market2. GPCRs constitute the largest and most diversefamily of heptahelical transmembrane receptors  that receive a signal (e.g. small peptides, lipid analogues, amino-acid derivatives, and sensory stimuli such as light, taste and odour2)from outside thecelland transmit this signal to the cell interior via interactions with G-proteins leading to activation of downstream effector systems4. In mammals 21 GÃŽ ±-subunits, six GÃŽ ²-subunits and twelve GÃŽ ³-subunits have been described5. Depending on their GÃŽ ± similarity, G-proteins are grouped into four main classes: GÃŽ ±s, GÃŽ ±i/o, GÃŽ ±q/11 and GÃŽ ±12/13 which show selectivity with respect to both, receptors and effectors due to the presence of recognition domains complementary to G-protein binding domains in receptors/effectors6. The main targets for G-proteins include adenylyl cyclase, phospholipase isoforms, Rho A/Rho kinases (a system that controls mainly signalling pathways involved in cell growth/proliferation), and the mitogen a ctivated protein kinase (involved in the control of many cell functions such as cell division), and ion channels7,8. In its inactivated state the complex is freely diffusible in the plane of the cell membrane due to fatty acid chain anchors on each subunit7. Stimulation of GPCRs by agonists leads to conformational changes in the receptor resulting in the acquirement of high affinity to the G(ÃŽ ±ÃŽ ²ÃŽ ³) complex. Due to their subsequent association, a GDP->GTP exchange in the ÃŽ ±-subunit will occur leading to dissociation of the G-protein complex from the receptor in form of a GÃŽ ±(GTP)-subunit and a GÃŽ ²ÃŽ ³-dimer. Prior the activation of the G-protein the GÃŽ ²ÃŽ ³-dimer is bound to a hydrophobic pocket present in GÃŽ ±-GDP. GTP binding to GÃŽ ± removes the hydrophobic pocket and reduces the affinity of GÃŽ ± for GÃŽ ²ÃŽ ³9. Both have a signalling function and can interact with various downstream effector systems 7,9. The duration of G protein-mediated effector activation is dependent on the intrinsic GTPase activity of the GÃŽ ±-subunit. GTP-hydrolysis results in dissociation of GÃŽ ±(GDP) f rom the effector to reunite with GÃŽ ²ÃŽ ³ completing the cycle7. Several studies have shown that the kinetics of G-protein signalling are regulated by RGS proteins that can not only act as GTPase activating proteins (GAPs) on GÃŽ ±-subunits hereby accelerating GTP-hydrolysis, but also as scaffolds to help assemble signalling complexes and providing a critical mechanism of regulation of cellular responses10. Over 30 RGS/RGS-like domain containing proteins have been described and classified into nine distinct subfamilies based on primary sequence homology and presence of additional domains, including the A/RZ (prototype RGSZ), the B/R4 (prototype RGS4), the C/R7 (prototype RGS7), the D/R12 (prototype RGS12), the E/RA (prototype Axin), the F/GEF, G/GRK, H/SNX and I/D-AKAP2 subfamilies3,10,11. They differ widely in their overall size and amino acid identity, and many family members possess a remarkable variety of structural domains and motifs that regulate their actions and/or enable them to interact with other binging partners with diverse cellular roles. RGS proteins have a highly conserved RGS domain of 120 amino acids3,11 which allows for selective binding to the transition state of GÃŽ ±(GTP->GDP+P)8 , accelerating the GTP-hydrolysis up to a 1000-fold5,10 by stabilising this transition. Some studies have shown that RGS proteins can also act as effector antagonists by binding tightly to GÃŽ ±(GTP), hereby blocking effector activation5,11. It has been suggested that simple RGS proteins (those of A/RZ and B/R4) have an almost exclusively negative regulatory function acting as modulators of G-protein signalling as for instance shown by the function of RGS4, an effective GAP protein for GÃŽ ±q family members. In mammalian cells RGS4 doesn’t block the receptor and GÃŽ ±q/11-directed inositol lipid/Ca2+ signalling completely but elicit rhythmic Ca2+ oscillations in mammalian cells10, 11. On the contrary, the larger RGS proteins can link active GÃŽ ±s to other signalling pathways and therefore serve as multifunctional integrators. Integration can occur via activation of kinases, recruitment of cellular scaffolds/associated proteins or by direct receptor interactions11. Two of the R12 family members (RGS12 and RGS14) were shown to coordinate components of the Ras/Raf/mitogen-activated protein kinase signalling pathway8,10. RGS proteins display specificity and selectivity in their interactions not only with G-proteins, but also GCPRs, ion channels and other signalling events3,5 which may be accomplished by firstly, differences in GAP activity towards different types of GÃŽ ±-subunits (e.g. RGS19 was shown to interact strongly with GÃŽ ±i1, GÃŽ ±i3 and GÃŽ ±o, weakly GÃŽ ±i2 but not with GÃŽ ±s and GÃŽ ±q5; secondly, the ability to interact with specific GPCRs or with effectors within the GPCR signalling axis directly, due to presence of characteristic structural domains and motifs (e.g. RGS2 and RGS4 bind selectively the 3rd intracellular loop of M2 and M5 muscarinic receptors5); thirdly, by formation of an RGS/G-protein complex that prevents the G-protein from binding its receptor or the downstream effectors; and lastly, by co-expression of the RGS-proteins with its target protein(s) in order for selective interactions to take place. An example is illustrated by the expression of the alternative splice d RGS9-1 and RGS9-2 in entirely different tissues, thus having different functions and selectivity for different targets. While RGS9-1 is expressed in the photoreceptor cell layers of the retina and is involved in the phototransduction pathway by regulation of photoreceptors, RGS9-2 is predominantly found in the brain and shows selectivity for the regulation of dopamine D2 and opioid  µ receptor signalling pathways5. RGS proteins play and essential regulatory role in G-protein mediated signal transduction, being able to regulate a great number of GCPR signalling events with great specificity and accuracy. By fully understanding the mechanisms and the significance of their expression, role and targets it can lead science to advances in the development of novel therapeutic drugs against disorders involving G-protein mediated signalling. References Baltoumas, F. A., Theodoropoulou, M. C., Hamodrakas, S.J.; Interactions of the a-subunits of heterotrimeric G-proteins with GPCRs, effectors and RGS proteins: A critical review and analysis of interacting surfaces, conformational shifts, structural diversity and electrostatic potentials. Journal of Structural Biology.2013;(182):209-218 Filmore, D.; Its a GPCR world. Modern Drug Discovery  (American Chemical Society).2004; (November): 24–28 Bansal, G., Druey, K.M., Xie, Z.; R4 RGS proteins: regulation of G-protein signaling and beyond. Pharmacology and Therapeutics. 2007;116(3):473-495 Joost, P., Methner, A.; Phylogenetic analysis of 277 human G-protein-coupled receptors as a tool for the prediction of orphan receptor ligands.Genome Biology. 2002;3(11): research0063.1–0063.16 Xie, G.X., Palmer, P.P.; How regulators of G protein signaling achieve selective regulation. Journal of molecular biology. 2007;366(2):349-365 CABRERA-VERA, T.M., VANHAUWE, J., THOMAS, T.O., MEDKOVA, M., PREININGER, A., MAZZONI, M.R., HAMM, H.; Insights into G Protein Structure, Function, and Regulation.  Endocrine Reviews. 2003;24(6):765-781 Rang, H.P., Dale, M.M., Ritter, J.M., Flower, R.J., Henderson, G.; Rang and Dales Pharmacology. 7th ed. UK. Elsevier Churchill Livingstone ; 2012; 3(32-33) Kimple, A.J., Bosch, D.E., Giguà ¨re, P.M., Siderovski, D.P.; Regulators of G-protein signaling and their GÃŽ ± substrates: promises and challenges in their use as drug discovery targets. Pharmacological Reviews. 2011;63(3):728-749 Oldham, W.M., Hamm, H.; Heterotrimeric G protein activation by G-protein-coupled receptors.NATURE REVIEWS | molecular cell biology. 2008;9:60-71 Keinan, D., Yang, S., Cohen, R.E., Yuan, X., Liu, T., Li, Y.P.; Role of regulator of G protein signaling proteins in bone.Front Biosci (Landmark Ed). 2014;1(19):634-648 Hollinger, S., Hepler, J.R.;. Cellular regulation of RGS proteins: modulators and integrators of G protein signaling.Pharmacological Reviews. 2002;54(3):527-559

Population Structure and Economic Implications of Kenya and China :: Papers

Population Structure and Economic Implications of Kenya and China In this piece of text I will be analysing and comparing the population structure and economic implications of two countries. The two countries that I have chosen are Kenya and China. China is a mixture of an LEDC and an MEDC whilst Kenya is a LEDC. You will be able to notice the difference when I give the facts and details of both countries. Population structure is such things as death rate and also birth rate and population spreads. It also shows the amount of people that are a certain age. The pyramid can also show the different trends and patterns of the age groups. Economic implications are the work force of the country and the industries in the countries. Country Status ============== China is a mixed between and LEDC and MEDC as said earlier, this is because the countries has a mixture of areas where some people are not as fortunate as others. The population of this country is around 1.3 billion. By looking at the map below you can see that it takes up a large space of Asia so there is no surprise that there is a lot of people living in the country. Here is a map to show where China is. [IMAGE] [IMAGE] Kenya on the other hand is an LEDC suffering from hunger, disease and dehydration. Kenya’s population is around 32 million which is much lower than China because of different death rates birth rates, infant mortality which will be explained later. Here is a map to show where Kenya is situated. A complete opposite to China in population size and status of the country. Death Rate ========== In China there is a small death rate of 7 per 1000 which is very low. The death rate is low because of reasons such as there is good health facilities which obviously means that people can be treated better

Christian Worldview Essay

Worldview Part I What is a worldview? â€Å"A worldview, is a response of our heart or inner being; our intellect, emotion or will. It is the total framework we bring to decision-making† (Weider & Gutierrez, 2011, p.51). An example is the Christian worldview. The way we as Christians behave should be in direct correlation with the teachings of Jesus as to how we should live our lives. People who hold to the Christian worldview should act as if everything they do matters. Many Christians these days do not act in a consistent manner to what their worldview is (Keener). Part II The question of Origin, Genesis 1:1 (ESV Bible) shows God creating the heavens and the earth in the beginning. â€Å"God is the infinite, personal, sovereign and good being who created the universe† (Lefebvre, 2011). Isaiah 45:18 (ESV Bible) describes how God created the heavens and formed the earth and create it and intended it to be inhabitated. The question of Identity- Genesis 1:27(ESV Bible) God created man in His own image. Psalm 139:14(ESV Bible) I am fearfully and wonderfully made. It is because we are made in God’s image that sets us apart from all other aspects of creation. This identity with God bestows upon us great distinction. We have to understand as clearly as possible what it means to be created in the image and likeness of God (Naugle, 2010). The Question of Meaning/Purpose- We as Christians believe that our purpose is to do the will of God. John 15:16(ESV Bible) we are appointed to go and bear fruit. In Matthew 28:19(ESV Bible) we are commanded to go and make disciples. Through-out the Bible, God has charged us with being the salt of the earth and light of the world, He has commanded us to go and compel them to come so that his house may be filled. As we can see our main purpose is to live a life that exemplifies Christ and leads others to Him. The Question of Morality- Romans 5:12-14(ESV Bible) sin entered the world. Romans 3:23(ESV Bible) we all have sinned and fall short of the Glory of God. God is the ultimate standard of morality and because of the depravity of man we cannot live up to His standard, thus needing redemption through the blood of the Lamb, Jesus Christ. The Question of Destiny- it is clear throughout the Bible about our final destination. John  3:16-17, John 5:13-14 (ESV Bible) and many other verses in the Bible make it clear that if we do not put our faith and trust in God and accept the gift of salvation that we will not spend eternal life with Him but rather burn in the lake of fire. God also makes it clear that the gift of salvation cannot be earned Eph. 2:8-9. Part III A biblical worldview should influence the way you think about, treat, and speak to others on a daily basis because we should treat people how we would want to be treated, Matthew 7:12 (ESV Bible). If we are to believe that God created us in His likeness and He commands us to go out and make disciples for Him then we would have to also believe that we should think, treat and speak to others in a Christ like manner on a daily basis. To not do so would make us as Christians look hypocritical in the eyes of non-believers. †¦.treat/interact with the environment and non-human creation? In Genesis 1:26(ESV Bible) God commands us to have dominion over the earth and subdue it. This does not mean that we can ravage the land and kill all the creatures on it. We are to be stewards of what God has given us and that includes the earth and the creatures on it. References Keener, D. (n.d.). What is a worldview?. Retrieved from http://www.dkeener.com/keenstuff/wv.html Lefebvre, M. (2011, April 02). Worldviews-christian. Retrieved from http://warrantedbelief.wordpress.com/2011/04/02/worldviews-christianity/ Naugle, D. (2010, February 14). Developing a biblical worldview. Retrieved from http://www.colsoncenter.org/the-center/columns/indepth/14423-developing-a-biblical-worldview Tackett, D. (n.d.). What’s a christian worldview?. Retrieved from http://www.focusonthefamily.com/faith/christian_worldview/whats_a_christian_worldview.aspx Weider, L., & Gutierrez, B. (2011). Consider. Virginia Beach: Academic Publishing Services, Inc.

Personal Statement And American Eagle Campaign Essay

Motivation drives us to accomplish our goals in life. A simple sentence such as I can get through this day. or I can become president. turns into the driving factor that helps us reach our destination. We all have used the I can statement and American Eagle has taken that statement to the next level in their #WeAllCan Campaign. The minute long video features a cast of celebrities in different settings throughout New York like Coney Island wearing a casual style of clothing. Black and white scenes intertwine with color scenes throughout the video, with even a vintage style of film shown. Through the credibility of the cast, the American Eagle Campaign effectively appeals to a target audience of millennials. The campaign uses pathos to create a cause of individuality and speaking out, but only uses those celebrities in a stereotypical way to sell the brand of clothes. This advertisement features a group of well-known millennials from our generation that give an immense amount of credibility to the commercial. It has role models of social media, music, television, and the fashion industry. Some actors that appear frequently are Troye Sivan, an out of the closet gay musician, Hailee Steinfeld, famous actor of Blackish, and Cody Christian, the recurring actor from Pretty Little Liars. This cast shows individuality and the new generation by having different races, sexual orientation, and gender. The ethos in the video attracts not only heteronormative buyers with theShow MoreRelatedBusiness Law Answers4935 Words   |  20 Pagesthis response with witnesses; sworn statements: a motion of summary judgement ï ¿ ½ Unit 2 Review: 1. In tort law, an actor who knows the substantial certainty that certainï ¿ ½consequences will result from an act has intent. TRUE 2. False imprisonment is a tort only if confinement is unjustified. TRUE 3. Mary is accused of slander. Slander includes: oral defamatory statements only 4. Leo hears Mona falsely accuse Nick of stealing from their employer. The statement is defamatory: because Leo heard itRead MoreMy Personal Experience With The Product2326 Words   |  10 Pages My Personal Experience with the Product I experienced my first taste of Miller Lite when I was an undergraduate student in college. The first time I ever purchased it was at a sports bar called O’Rielys in Chicago. Miller Lite is a light lager style beer that has a taste of graininess with hints of grain husk, sweetness, light toasted malt and a trace of citrus and pine. Miller Lite is a crystal clear, light golden yellow color liquid. The aroma smells like hoppy bread and it is served coldRead MoreNra1731 Words   |  7 Pagessmall vote for the NRA. Theyre good citizens. They call their Congressmen. They write. They vote. They contribute. And they get what they want over time.(qtd. in nra.org) The NRA is indeed all of these things, with programs to benefit a variety of Americans, sponsorship of one of Americas oldest sports, and as an organization that will stand up for its political beliefs regarding the Second Amendment. (www.nra.org) Formed in 1872 when military leaders were disappointed with the marksmanship of theirRead MoreAF Case5347 Words   |  22 Pagesadvertising because this can also affect the market of AF. IV. Situation Analysis: A. Environment 1. Economic Conditions and Trends The fashion industry is famous for a variety of retail channels such as specialty stores. Gap, American Eagle, J.Crew and Abercrombie Fitch to name a few. In 2003, specialty stores accounted 28.5 percent of all retail sales. In 2005, Abercrombie Fitch has been steadily declining from their inventory turnover ratio when it declined from 4.49 in 2005Read MoreMain Features of the New Deal Essay1683 Words   |  7 Pagesand get Americans earning money again, to protect peoples savings, homes and livelihoods, to provide relief for the ill, the elderly and the unemployed and to get American industry and agriculture running once again. In his first hundred days in charge in charge Roosevelt worked tirelessly to transform America, using new laws, acts and the full power of the government to steer America out of the depression. His first objective was to restore Americans confidence inRead MoreMarketing Assignment Anf6424 Words   |  26 Pagesthe Central American countries of Costa Rica, Dominican Republic, El Salvador, Guatemala, Honduras, and Nicaragua. (Open CRS, 2005) This free trade agreement is favorable for apparel manufacturers as it allows tariff free access to the labor market in Central American. Apparel industries can outsource their labor and manufacturing to Central American markets instead of the markets overseas. (Open CRS, 2005) Canada has proposed a similar agreement called the Canada Central American Free Trade AgreementRead MoreCase Study, Gap Inc.2807 Words   |  12 Pagesprovides clothing, accessories, and personal care products for men, women, children, and babies. The first store was opened by Doris and Don Fisher in 1969. Gap also owns Old Navy, Banana Republic, Piperlime, and Athletica brands. The company provides a wide range of family clothing products including denim, khak is, t-shirts, fashion apparel, shoes, accessories, intimate apparel, and personal care product. Mission Statement Gap has no formal vision or mission statement, but the company does have philosophyRead MoreThe National Rifle Association (NRA) Essay1774 Words   |  8 Pagessmall vote for the NRA. Theyre good citizens. They call their Congressmen. They write. They vote. They contribute. And they get what they want over time.(qtd. in nra.org) The NRA is indeed all of these things, with programs to benefit a variety of Americans, sponsorship of one of Americas oldest sports, and as an organization that will stand up for its political beliefs regarding the Second Amendment. (www.nra.org) Formed in 1872 when military leaders were disappointed with the marksmanship of theirRead MoreAbercrombie And Fitch s Current Csr Policies And Activities2372 Words   |  10 Pages Introduction Abercrombie and Fitch, founded in 1892, is an American clothing company that targets young customers. It is headquartered in New Albany, Ohio, and has over 250 locations in the United States and is expanding internationally. Abercrombie and Fitch is a reputable apparel and lifestyle brand. However, in the past few years, the company’s image has been battered by accusations of discrimination toward minority groups. In this report, I will describe and analyze Abercrombie and Fitch’sRead MoreGap Imc Plan3891 Words   |  16 Pagesin selling clothing, accessories and personal care products. When Gap was founded in 1969, its targeted customers were younger generations (hence the name of the store, which refers to the generation gap of the time). Gap s originally sold signature blue jeans and white cotton t-shirts, but later expanded to include clothing for men, women and children. The product line of the company includes casual apparel like denim, khakis and T-shirts; footw ear, personal care products, accessories and fashion